CN102949356A - Thymalfasin-containing freeze-dried preparation - Google Patents

Thymalfasin-containing freeze-dried preparation Download PDF

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CN102949356A
CN102949356A CN2012104998304A CN201210499830A CN102949356A CN 102949356 A CN102949356 A CN 102949356A CN 2012104998304 A CN2012104998304 A CN 2012104998304A CN 201210499830 A CN201210499830 A CN 201210499830A CN 102949356 A CN102949356 A CN 102949356A
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thymalfasin
lyophilized formulations
mentioned gained
following composition
solution
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CN102949356B (en
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李宝齐
董凯
孙长海
姚小青
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Tianjin Chase Sun Pharmaceutical Co Ltd
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Tianjin Chase Sun Pharmaceutical Co Ltd
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Abstract

The invention relates to a thymalfasin-containing freeze-dried preparation. The freeze-dried preparation is prepared from thymalfasin serving as an active ingredient and pharmaceutically-acceptable auxiliary materials. Tert-butyl alcohol is added into a prescription, and the pH value of a solution is adjusted by adopting an acetate buffer solution before freeze drying, so that the freeze drying period is shortened, degradation of main medicaments in a preparation process is suppressed, the stability of main medicaments is enhanced, and the quality of a product is ensured.

Description

A kind of lyophilized formulations that contains thymalfasin
Technical field
The invention belongs to medical technical field, be specifically related to lyophilized formulations of thymalfasin and preparation method thereof.
Background technology
Thymalfasin (Thymalfasin), also be referred to as thymosin a1, thymosin al, its aminoacid sequence is: N-Acetyl-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu.-Ala-Glu-Asn-OH, molecular formula is: C 129H 215N 33O 35, molecular weight is: 3108.280.
Figure BDA0000248583571
The injection thymalfasin is that commodity are called ZADAXIN by the medicine that is used for the treatment of hepatitis B and raising immunity of SciClone Pharmaceuticals International company exploitation, and domestic have the injection thymalfasins such as Ji Tai, Mai Puxin and day to go on the market.
SciClone Pharmaceuticals International has announced said preparation constituent in the injection thymalfasin description of its Italy's listing be mannitol, sodium dihydrogen phosphate-water, seven hypophosphite monohydrate disodium hydrogens, the water for injection that also comprises one bottle of 1.0ml in this external packing is used for dissolving in use this lyophilized formulations.Said preparation as the lyophilizing support, forms pH value that phosphate buffer keep drug solution with sodium dihydrogen phosphate-water and seven hypophosphite monohydrate disodium hydrogens with mannitol, makes it stable.
The injection thymalfasin needs under the condition of 2～8 ℃ of preservations, and import standard JX19990203 and version Chinese Pharmacopoeia in 2010 stipulate that the total amount of its related substance must not surpass 4%, and single impurity must not surpass 2%.The injection thymalfasin need to be prepared its dosing link of fill liquid guarantee with 2～8 ℃ water for injection and not produce a large amount of related substances on production link; Need cold chain transportation in intermediate links, its related substance of guarantee does not exceed the regulation of standard.
Chinese patent 200610020134.5 provides a kind of thymosin a1 injection, it comprises approximately O.02%～1.0% (W/V) thymosin a1, about O.02%～5.0% (W/V) buffer agent, about O.5%～5.0% (W/V) isoosmotic adjusting agent, about 0.5%～about 5.0% (W/V) stabilizing agent, and the pH of described injection is 5.0～7.5.Described buffer agent is selected from sodium hydrogen phosphate, sodium hydroxide, sodium carbonate and ammonia, and preferred reducing is sodium hydrogen phosphate, and described buffer agent can use separately or unite use.Described isoosmotic adjusting agent is selected from carbohydrate, polyhydric alcohol; Wherein carbohydrate is selected from galactose, arabinose, lactose; Polyhydric alcohol is from mannitol, sorbitol, inositol, glycerol, xylitol and Polyethylene Glycol; Preferred isoosmotic adjusting agent is mannitol, and described isoosmotic adjusting agent can use separately or unite use.Described stabilizing agent is selected from glycine, glutamic acid, ammonium acetate, and preferred stabilizer is glycine, and described stabilizing agent can use separately and or unite use.Described anti-microbial preservative is selected from metacresol etc., and preferred anti-microbial preservative is metacresol, and described anti-microbial preservative can use separately or unite use.The stability of this patent is not fine, obviously increases through the long-time rear impurity content of placing.
Summary of the invention
The object of the present invention is to provide a kind of good stability, thymalfasin lyophilized formulations that bioavailability is high.
Thymalfasin lyophilized formulations of the present invention comprises following composition:
With 0.5M acetic acid or sodium acetate regulator solution pH value, to 5.5-6.5.
Concrete, thymalfasin lyophilized formulations of the present invention consists of the following composition:
With 0.5M acetic acid or sodium acetate regulator solution pH value, to 5.5-6.5.
Another object of the present invention is to provide the preparation method of thymalfasin lyophilized formulations.
Preparation method of the present invention may further comprise the steps:
Step 1. is got recipe quantity 50% water for injection, adds successively the tert-butyl alcohol, mannitol, and sodium acetate stirs, and makes dissolving.
Step 2. is got the recipe quantity thymalfasin and is joined in the above-mentioned gained solution, stirs, and makes fully dissolving.
Step 3. is with 0.5M acetic acid or sodium acetate regulator solution pH value, to 5.5-6.5.
Step 4. with the above-mentioned gained solution of water for injection standardize solution to 1000ml.
Step 5. filters above-mentioned gained medicinal liquid molecular cut off to be housed as 5000 daltonian cross-flow ultrafiltration systems, the microorganism of removing thermal source and may exist, and detect wherein thymalfasin content.
Step 6. is sub-packed in above-mentioned gained medicinal liquid in the colourless middle Pyrex control bottle of 1ml, partly jumps a queue.
Step 7. is opened freeze dryer with the above-mentioned glass tube vial that medicinal liquid the is housed freeze dryer cold-trap of packing into.
Step 8. was set freeze-drying curve and is carried out lyophilizing, was cooled to-40 ℃ through 1.5 hours, and-40 ℃ of pre-freezes are evacuated to 8-10Pa,
Be warming up to-15 ℃, carry out primary drying, after the end, be warming up to 20 ℃ through 1 hour again, carry out redrying, inflated with nitrogen after lyophilizing finishes, the total head plug rolls lid and get final product.
Prescription of the present invention is to obtain through a large amount of experiment screenings, the unexpected discovery by after an amount of tert-butyl alcohol of adding, lyophilized formulations stability is improved significantly, and is embodied in after 6 months accelerated stability tests, and maximum single contaminant and total impurities all increase in the sample.The simultaneously adding of acetate buffer so that fungistatic effect of the present invention be improved.The characteristics such as the present invention also has few side effects, and is evident in efficacy, the present invention can obviously shorten lyophilization cycle with respect to prior art, and using water wisely and electricity consumption reduce cost, are fit to large-scale production.
The specific embodiment
By following embodiment prescription of the present invention and technique are described, but the present invention is not limited to following embodiment.
Embodiment 1.
Prescription:
Preparation method:
1. get recipe quantity 50% water for injection, add successively the tert-butyl alcohol, mannitol, sodium acetate stirs, and makes dissolving.
2. get the recipe quantity thymalfasin and join in the above-mentioned gained solution, stir, make fully dissolving.
3. with 0.5M acetic acid or sodium acetate regulator solution pH value, to 5.5-6.5.
With the above-mentioned gained solution of water for injection standardize solution to 1000ml.
5. molecular cut off to be housed as 5000 daltonian cross-flow ultrafiltration systems, filter above-mentioned gained medicinal liquid, the microorganism of removing thermal source and may exist, and detect wherein thymalfasin content.
6. above-mentioned gained medicinal liquid is sub-packed in the colourless middle Pyrex control bottle of 1ml, partly jumps a queue.
7. the freeze dryer cold-trap of the above-mentioned glass tube vial that medicinal liquid is housed being packed into is opened freeze dryer.
8. set freeze-drying curve and carry out lyophilizing, be cooled to-40 ℃ through 1.5 hours ,-40 ℃ of pre-freezes are evacuated to 8-10Pa, be warming up to-15 ℃, carry out primary drying, after the end, be warming up to 20 ℃ through 1 hour again, carry out redrying, inflated with nitrogen after lyophilizing finishes, the total head plug rolls lid and get final product.
Embodiment 2.
Prescription:
Figure BDA0000248583575
Preparation method:
1. get recipe quantity 50% water for injection, add successively the tert-butyl alcohol, mannitol, sodium acetate stirs, and makes dissolving.
2. get the recipe quantity thymalfasin and join in the above-mentioned gained solution, stir, make fully dissolving.
3. with 0.5M acetic acid or sodium acetate regulator solution pH value, to 5.5-6.5.
With the above-mentioned gained solution of water for injection standardize solution to 1000ml.
5. molecular cut off to be housed as 5000 daltonian cross-flow ultrafiltration systems, filter above-mentioned gained medicinal liquid, the microorganism of removing thermal source and may exist, and detect wherein thymalfasin content.
6. above-mentioned gained medicinal liquid is sub-packed in the colourless middle Pyrex control bottle of 1ml, partly jumps a queue.
7. the freeze dryer cold-trap of the above-mentioned glass tube vial that medicinal liquid is housed being packed into is opened freeze dryer.
8. set freeze-drying curve and carry out lyophilizing, be cooled to-40 ℃ through 1.5 hours ,-40 ℃ of pre-freezes are evacuated to 8-10Pa, be warming up to-15 ℃, carry out primary drying, after the end, be warming up to 20 ℃ through 1 hour again, carry out redrying, inflated with nitrogen after lyophilizing finishes, the total head plug rolls lid and get final product.
Embodiment 3.
Prescription:
Figure BDA0000248583576
Preparation method:
1. get recipe quantity 50% water for injection, add successively the tert-butyl alcohol, mannitol, sodium acetate stirs, and makes dissolving.
2. get the recipe quantity thymalfasin and join in the above-mentioned gained solution, stir, make fully dissolving.
3. with 0.5M acetic acid or sodium acetate regulator solution pH value, to 5.5-6.5.
With the above-mentioned gained solution of water for injection standardize solution to 1000ml.
5. molecular cut off to be housed as 5000 daltonian cross-flow ultrafiltration systems, filter above-mentioned gained medicinal liquid, the microorganism of removing thermal source and may exist, and detect wherein thymalfasin content.
6. above-mentioned gained medicinal liquid is sub-packed in the colourless middle Pyrex control bottle of 1ml, partly jumps a queue.
7. the freeze dryer cold-trap of the above-mentioned glass tube vial that medicinal liquid is housed being packed into is opened freeze dryer.
8. set freeze-drying curve and carry out lyophilizing, be cooled to-40 ℃ through 1.5 hours ,-40 ℃ of pre-freezes are evacuated to 8-10Pa, be warming up to-15 ℃, carry out primary drying, after the end, be warming up to 20 ℃ through 1 hour again, carry out redrying, inflated with nitrogen after lyophilizing finishes, the total head plug rolls lid and get final product.
Embodiment 4.
Prescription:
Figure BDA0000248583577
Preparation method:
1. get recipe quantity 50% water for injection, add successively the tert-butyl alcohol, mannitol, sodium acetate stirs, and makes dissolving.
2. get the recipe quantity thymalfasin and join in the above-mentioned gained solution, stir, make fully dissolving.
3. with 0.5M acetic acid or sodium acetate regulator solution pH value, to 5.5-6.5.
With the above-mentioned gained solution of water for injection standardize solution to 1000ml.
5. molecular cut off to be housed as 5000 daltonian cross-flow ultrafiltration systems, filter above-mentioned gained medicinal liquid, the microorganism of removing thermal source and may exist, and detect wherein thymalfasin content.
6. above-mentioned gained medicinal liquid is sub-packed in the colourless middle Pyrex control bottle of 1ml, partly jumps a queue.
7. the freeze dryer cold-trap of the above-mentioned glass tube vial that medicinal liquid is housed being packed into is opened freeze dryer.
8. set freeze-drying curve and carry out lyophilizing, be cooled to-40 ℃ through 1.5 hours ,-40 ℃ of pre-freezes are evacuated to 8-10Pa, be warming up to-15 ℃, carry out primary drying, after the end, be warming up to 20 ℃ through 1 hour again, carry out redrying, inflated with nitrogen after lyophilizing finishes, the total head plug rolls lid and get final product.
Below data further specify beneficial effect of the present invention by experiment:
A. the adding of the tert-butyl alcohol is on the impact of preparation freeze-drying time:
Prepare respectively the lyophilized formulations that contains and do not contain the tert-butyl alcohol by embodiment 1 prescription and technique, it is as shown in the table to obtain each step time of lyophilizing:
Figure BDA0000248583578
B. 6 months accelerated stability data of each embodiment sample
Prepare respectively thymalfasin lyophilized formulations sample by embodiment 1.At 25 ℃ ± 2 ℃, relevant nature is measured respectively in 60% ± 5%RH storage, obtains related data, and is as shown in the table:
Prepare respectively thymalfasin lyophilized formulations sample by embodiment 2.At 25 ℃ ± 2 ℃, relevant nature is measured respectively in 60% ± 5%RH storage, obtains related data, and is as shown in the table:
Figure BDA00002485835710
Prepare respectively thymalfasin lyophilized formulations sample by embodiment 3.At 25 ℃ ± 2 ℃, relevant nature is measured respectively in 60% ± 5%RH storage, obtains related data, and is as shown in the table:
Prepare respectively thymalfasin lyophilized formulations sample by embodiment 4.At 25 ℃ ± 2 ℃, relevant nature is measured respectively in 60% ± 5%RH storage, obtains related data, and is as shown in the table:
Figure BDA00002485835712
Find that in the acceleration for stabilization Journal of Sex Research thymalfasin lyophilized formulations of the present invention's preparation has better stability than the thymalfasin lyophilized formulations that has now gone on the market, and is mainly reflected in maximum single contaminant and the total impurities check item of preparation.The thymalfasin lyophilized formulations that adopts this patent method to produce is few in accelerated stability test rear impurity recruitment, regulation (total amount of related substance must not surpass 4%, and single impurity must not surpass 2%) in thymalfasin lyophilized formulations import standard JX19990203 and the version Chinese Pharmacopoeia in 2010.
And adopt the tertiary butanol and water cosolvent system as freezing solvent, by test relatively, freeze-drying time can be obviously shortened in discovery, reduces energy loss, increases economic efficiency.
Acetic acid itself is as antibacterial in addition, and the constituent as buffer solution in the present invention's prescription adds, and still can bring into play itself intrinsic bacteriostasis, avoided the adding of other antibacterial, at solution preparation, reach in the use procedure simultaneously, reduced the probability of medicinal liquid microbiological contamination.

Claims (7)

1. lyophilized formulations that contains thymalfasin comprises following composition:
2. lyophilized formulations according to claim 1 consists of the following composition:
Figure FDA0000248583562
3. lyophilized formulations according to claim 1 and 2 is characterized in that, with 0.5M acetic acid or sodium acetate regulator solution pH value, to 5.5-6.5.
4. lyophilized formulations according to claim 1 is characterized in that, consists of the following composition:
5. lyophilized formulations according to claim 1 is characterized in that, consists of the following composition:
Figure FDA0000248583564
6. lyophilized formulations according to claim 1 is characterized in that, consists of the following composition:
Figure FDA0000248583565
7. the preparation method of lyophilized formulations claimed in claim 1 may further comprise the steps:
Step 1. is got recipe quantity 50% water for injection, adds successively the tert-butyl alcohol, mannitol, and sodium acetate stirs, and makes dissolving;
Step 2. is got the recipe quantity thymalfasin and is joined in the above-mentioned gained solution, stirs, and makes fully dissolving;
Step 3. is with 0.5M acetic acid or sodium acetate regulator solution pH value, to 5.5-6.5;
Step 4. with the above-mentioned gained solution of water for injection standardize solution to 1000ml;
Step 5. filters above-mentioned gained medicinal liquid molecular cut off to be housed as 5000 daltonian cross-flow ultrafiltration systems, the microorganism of removing thermal source and may exist, and detect wherein thymalfasin content;
Step 6. is sub-packed in above-mentioned gained medicinal liquid in the colourless middle Pyrex control bottle of 1ml, partly jumps a queue;
Step 7. is opened freeze dryer with the above-mentioned glass tube vial that medicinal liquid the is housed freeze dryer cold-trap of packing into;
Step 8. was set freeze-drying curve and is carried out lyophilizing, was cooled to-40 ℃ through 1.5 hours, and-40 ℃ of pre-freezes are evacuated to 8-10Pa,
Be warming up to-15 ℃, carry out primary drying, after the end, be warming up to 20 ℃ through 1 hour again, carry out redrying, inflated with nitrogen after lyophilizing finishes, the total head plug rolls lid and get final product.
CN201210499830.4A 2012-11-28 2012-11-28 Thymalfasin-containing freeze-dried preparation Active CN102949356B (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104587452A (en) * 2015-01-21 2015-05-06 上海苏豪逸明制药有限公司 Solution for preparing thymalfasin preparation and method for preparing thymalfasin preparation by virtue of solution
CN104856965A (en) * 2015-05-29 2015-08-26 湖南科伦制药有限公司 Freeze-drying method of thymosin for injection

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CN101683519A (en) * 2008-08-25 2010-03-31 海南中和多肽药物研发有限公司 Composition of thymic peptide alpha 1 and thymopeptide-5 and preparation method thereof
CN102247319A (en) * 2011-08-03 2011-11-23 海南中和药业有限公司 Thymalfasin-containing medicinal composition and preparation method thereof
CN102441160A (en) * 2011-12-16 2012-05-09 深圳市健元医药科技有限公司 Thymosin alpha1 medicinal composition and preparation method thereof

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CN101683519A (en) * 2008-08-25 2010-03-31 海南中和多肽药物研发有限公司 Composition of thymic peptide alpha 1 and thymopeptide-5 and preparation method thereof
CN102247319A (en) * 2011-08-03 2011-11-23 海南中和药业有限公司 Thymalfasin-containing medicinal composition and preparation method thereof
CN102441160A (en) * 2011-12-16 2012-05-09 深圳市健元医药科技有限公司 Thymosin alpha1 medicinal composition and preparation method thereof

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104587452A (en) * 2015-01-21 2015-05-06 上海苏豪逸明制药有限公司 Solution for preparing thymalfasin preparation and method for preparing thymalfasin preparation by virtue of solution
CN104587452B (en) * 2015-01-21 2017-06-23 上海苏豪逸明制药有限公司 A kind of solution for preparing thymalfasin preparation and the method that thymalfasin preparation is prepared using the solution
CN104856965A (en) * 2015-05-29 2015-08-26 湖南科伦制药有限公司 Freeze-drying method of thymosin for injection
CN104856965B (en) * 2015-05-29 2018-07-20 湖南科伦制药有限公司 A kind of freeze drying process of injection thymic peptide

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